Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats

Qiu, Huiliang; Liu, Wei; Lan, Tsuo Hung; Pan, Wenjun; Chen, Xiaoling; Wu, Huanlin; Xu, Danping

doi:10.1016/j.phymed.2018.09.238

Cited by 77 publications

(48 citation statements)

References 29 publications

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“…When TGF-b1 binds to its heterodimeric receptor complex, TGF-bRI and TGF-bRII, the downstream canonical Smads signaling cascades are activated. The signaling molecules Smad2/3 are more dedicated downstream effectors of the classical TGF-b1 pathway in the initiation and progression of cardiac fibrosis [29][30][31]. Hence, we used Smad2/3 activation as an indicator of the TGF-b1 pathway.…”

Section: Discussionmentioning

confidence: 99%

Doxycycline Improves Fibrosis-Induced Abnormalities in Atrial Conduction and Vulnerability to Atrial Fibrillation in Chronic Intermittent Hypoxia Rats

Zhang

Wang

et al. 2020

Med Sci Monit

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Background: The structural remodeling of atrial architecture, especially increased amounts of fibrosis, is a critical substrate to atrial fibrillation (AF). Doxycycline (Doxy) has recently been shown to exert protective effects against fibrogenic response. This study investigated whether doxycycline (Doxy) can sufficiently ameliorate the fibrosis-induced changes of atrial conduction and AF vulnerability in a chronic intermittent hypoxia (CIH) rat model. Material/Methods: Sixty rats were randomized into 3 groups: Control, CIH, and CIH with Doxy treatment (DOXY) group. CIH rats were exposed to CIH (6 h/d) and Doxy-treated rats were treated with Doxy during processing CIH. After 6 weeks, echocardiographic and hemodynamic parameters were measured. Isolated atrial epicardial activation mapping and heart electrophysiology were performed. The extent of atrial interstitial fibrosis were estimated by Masson's trichrome staining. The expression levels of TGF-b1 and downstream factors were determined by real-Time PCR, immunohistochemistry, and Western blot analysis. Results: Compared to Control rats, the CIH rats showed significant atrial interstitial fibrosis, longer inter-atrial conduction time, and elevated conduction inhomogeneity and AF inducibility, and the expression of TGF-b1, TGF-bRI, TGF-bRII, P-Smad2/3, a-SMA, CTGF, and Collagen I were significantly increased, whereas the velocity of atrial conduction and the expression of miR-30c were dramatically decreased. All of these changes were significantly improved by Doxy treatment. Conclusions: The findings suggested that Doxy can profoundly mitigate atrial fibrosis, conduction inhomogeneity as well as high AF inducibility secondary to fibrosis in a CIH rat model through suppressing the TGF-b1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Doxycycline Improves Fibrosis-Induced Abnormalities in Atrial Conduction and Vulnerability to Atrial Fibrillation in Chronic Intermittent Hypoxia Rats

Zhang

Wang

et al. 2020

Med Sci Monit

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“…The prolongation of IACT and P wave duration usually represents the interatrial block and enlarged atria, while fibrosis inhibition may explain subdued atrial ERP and IACT prolongation. 29,33) Recent research, focused on exploring the role of anti-inflammatory and anti-fibrotic treatment, have approved AF prevention following MI, 33,34) but we also can't ignore the effect of reducing AF by improving atrial expansion and cardiac dysfunction. Regard-ing the relationship between AF and AERP, some studies considered that AERP was shortened in some models, including rapid atrial pacing 35,36) and early phage of MI (< 45 minutes) model, 37) but AERP was prolonged in longterm MI model (four weeks).…”

Section: Discussionmentioning

confidence: 99%

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

Liu

Shen

et al. 2019

Int. Heart J.

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Atrial inflammation and fibrosis are the critical processes involved in atrial fibrillation (AF) after myocardial infarction (MI). Fisetin is a dietary flavonoid that has shown forceful anti-inflammatory and antiproliferative properties in diverse models of disease. However, fisetin's role in atrial inflammation, fibrosis, and AF vulnerability post-MI remains completely unknown. Rats were subjected to MI surgery, by left anterior descending coronary artery ligation or sham operation, and treated with DMSO or fisetin via intraperitoneal injection. After 28 days, echocardiographic parameters were performed, and AF inducibility was tested. We further evaluated the inflammation, fibrosis of left atria (LA), and related signal pathways by RT-PCR, Western blot, and staining analysis. Compared to the MI group, fisetin treatment improved cardiac function, inhibited macrophage recruitment into the LA and production of IL-1β and TNF-α, and attenuated adverse atrial fibrosis following acute myocardial infarction (AMI). Electrophysiological recordings, using an isolated perfused heart, showed that MI-induced higher inducibility of AF and prolonged AF duration, interatrial conduction time (IACT), atrial effective refractory period (AERP) were significantly alleviated by fisetin. Mechanistically, fisetin markedly increased phosphorylated AMPK (p-AMPK) levels and suppressed NF-κB p65, p38MAPK, and smad3 phosphorylation in the LA post-MI. We demonstrate that fisetin improves LA expansion, cardiac function, atrial inflammation, fibrosis, and vulnerability to AF following MI by possibly regulating AMPK/NF-κB p65 and p38MAPK/smad3 signaling pathways.

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“…The Visual Sonics Vevo 2100 system (VisualSonics Inc., Toronto, Canada) was used to assess cardiac function and the structure at the baseline, 3 months after surgery, as described previously (Qiu et al, 2018a,b). Animals were anesthetized with isoflurane (2%).…”

Section: Methodsmentioning

confidence: 99%

Chronic Kidney Disease Increases Atrial Fibrillation Inducibility: Involvement of Inflammation, Atrial Fibrosis, and Connexins

Qiu

Liu

et al. 2018

Front. Physiol.

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Chronic kidney disease (CKD) causes atrial structural remodeling and subsequently increases the incidence of atrial fibrillation (AF). Atrial connexins and inflammatory responses may be involved in this remodeling process. In this study, nephrectomy was used to produce the CKD rat model. Three months post-nephrectomy, cardiac structure, function and AF vulnerability were quantified using echocardiography and electrophysiology methods. The left atrial tissue was tested for quantification of fibrosis and inflammation, and for the distribution and expression of connexin (Cx) 40 and Cx43. An echocardiography showed that CKD resulted in the left atrial enlargement and left ventricular hypertrophy, but had no functional changes. CKD caused a significant increase in the AF inducible rate (91.11% in CKD group vs. 6.67% in sham group, P < 0.001) and the AF duration [107 (0–770) s in CKD vs. 0 (0–70) s in sham, P < 0.001] with prolonged P-wave duration. CKD induced severe interstitial fibrosis, activated the transforming growth factor-β1/Smad2/3 pathway with a massive extracellular matrix deposition of collagen type I and α-smooth muscle actin, and matured the NLR (nucleotide-binding domain leucine-rich repeat-containing receptor) pyrin domain-containing protein 3 (NLRP3) inflammasome with an inflammatory cascade response. CKD resulted in an increase in non-phosphorylated-Cx43, a decrease in Cx40 and phosphorylated-Cx43, and lateralized the distribution of Cx40 and Cx43 proteins with upregulations of Rac-1, connective tissue growth factor and N-cadherin. These findings implicate the transforming growth factor-β1/Smad2/3, the NLRP3 inflammasome and the connexins as potential mediators of increased AF vulnerability in CKD.

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Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-β1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats

Cited by 77 publications

References 29 publications

Doxycycline Improves Fibrosis-Induced Abnormalities in Atrial Conduction and Vulnerability to Atrial Fibrillation in Chronic Intermittent Hypoxia Rats

Doxycycline Improves Fibrosis-Induced Abnormalities in Atrial Conduction and Vulnerability to Atrial Fibrillation in Chronic Intermittent Hypoxia Rats

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

Chronic Kidney Disease Increases Atrial Fibrillation Inducibility: Involvement of Inflammation, Atrial Fibrosis, and Connexins

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